Heteroaryls and uses thereof

• US 10,202,373 B2
• Filed: 01/13/2015
• Issued: 02/12/2019
• Est. Priority Date: 01/14/2014
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Bharathan, Indu T., Blackburn, Chris, Ciavarri, Jeffrey P., Chouitar, Jouhara, Cullis, Courtney A., D'Amore, Natalie, Fleming, Paul E., Gigstad, Kenneth M., Gipson, Krista E., Girard, Mario, Hu, Yongbo, Lee, Janice, Li, Gang, Rezaei, Mansoureh, Sintchak, Michael D., Soucy, Francois, Stroud, Stephen G., Vos, Tricia J., Xu, He, Ye, Yingchun
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US15/111,429
• Publication Number:
  US 20160333007A1
• Time in Patent Office: 1,491 Days
• Field of Search: 546113, 514300
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides a compound of formula I:

• • wherein R¹, X¹, X², R², R³, R⁴, R⁵, n, and m are as described in the specification. Such compounds are inhibitors of VPS34 and thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

Claims

1. A compound of formula I:

2. The compound or a pharmaceutically acceptable salt of claim 1, wherein R¹ is -L²-R⁶.

3. The compound or a pharmaceutically acceptable salt of claim 2, wherein L¹ is —

C(O)—

or —

C(O)O—

.

4. The compound or a pharmaceutically acceptable salt of claim 2, wherein X¹ and X² are both CH.

5. The compound or a pharmaceutically acceptable salt of claim 2, wherein L² is —

C(O)—

or —

S(O)₂—

.

6. The compound or a pharmaceutically acceptable salt of claim 2, wherein R⁶ is methyl, ethyl, or phenyl optionally substituted with 1-3 groups selected from halo or C_1-3 alkyl.

7. The compound or a pharmaceutically acceptable salt of claim 2, wherein R² is hydrogen.

8. The compound or a pharmaceutically acceptable salt of claim 2, wherein R³ is C_1-3 alkyl.

9. The compound or a pharmaceutically acceptable salt of claim 2, wherein L¹ is a bond.

10. The compound or a pharmaceutically acceptable salt of claim 2, wherein R⁴ is substituted at the ring position between the ring nitrogen and the ring carbon connected to —

N(R¹)—

.

11. The compound or a pharmaceutically acceptable salt of claim 1 with formula (II) below:

12. The compound or a pharmaceutically acceptable salt of claim 11, wherein R⁶ is C_1-4 alkyl, 3-6-membered cycloaliphatic, phenyl, or naphthyl;

R³ is C_1-3 alkyl; and

R⁴ is halo or -L⁴-R⁹, wherein L⁴ is C_1-4 alkylene chain, —

O—

, or —

N(R^e)—

, and wherein R^e is hydrogen or methyl, and R⁹ is hydrogen or C_1-3 alkyl.

13. The compound or a pharmaceutically acceptable salt of claim 11, wherein R⁶ is methyl, ethyl, cyclopropyl, or phenyl optionally substituted with C_1-3 alkyl, fluoro, or chloro.

15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable carrier.

14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is one of: